The use of microparticles and nanoparticles for drug delivery is well known in the art. Specifically, microsphere and nanosphere-based polymeric drug delivery systems have great potential as oral delivery systems due to their ability to protect encapsulated active agents from the harsh gastrointestinal tract. Although significant effort has focused on developing effective delivery systems for translation into clinical use, significant obstacles exist in the development of effective nanoparticles for oral drug delivery.
One significant obstacle facing microsphere and nanosphere-based oral delivery systems is achieving high enough levels of uptake to reach therapeutic concentrations of the encapsulated drugs after administration. A variety of strategies have been evaluated to enhance the translocation of particles from the intestinal lumen, most with limited success. One potential method of enhancing uptake is to employ polymers with bioadhesive properties. In theory, incorporating such polymers will result in particles which adhere to the mucous membrane proximal to the intestinal cells, and increase the transit time of the particles in the gastrointestinal tract. While many hydrogel-based bioadhesive platforms have shown promise for oral drug delivery systems (Ponchel, et al. Adv Drug Deliv Rev. 34:191-219 (1998)), their success has been limited due to the rapid release of drugs upon aqueous swelling as well as difficulties associated with loading hydrophilic drugs into the hydrogels. In addition, bioadhesive polymer chains often become physically entangled in the mucus, impeding the translocation of the particles in the gastrointestinal tract. Peppas, et al., Biomaterials, 17:1553-61 (1996).
Another obstacle facing microsphere and nanosphere-based oral delivery systems is providing accurate control of drug release kinetics. Microparticles and nanoparticles often exhibit burst release, i.e., release of a large amount of the encapsulated drug shortly after administration of the particles. Burst release occurs because some of the drug to be encapsulated adheres to the surface of the particle during preparation and/or some of the drug diffuses to the surface prior to administration. Upon administration, the drug on the surface is released almost immediately since there is no layer or coating to control release of the drug.
In order to overcome burst release phenomena, microparticles and nanoparticles have been coated with controlled release coatings using conventional coating techniques. While such techniques have been used to successfully coat microparticles, it has been a challenge to modify these techniques to effectively coat nanoparticles due to their smaller size.
Alternatives to coating nanoparticles using conventional coating techniques include methods for preparing multiwall nanoparticles in situ. However, many of these techniques require multiple relatively complicated steps. For example, U.S. Pat. No. 5,912,017 to Mathiowitz, et al., describes methods for making multi-walled microspheres. Two polymers are dissolved in a volatile organic solvent. The substance to be encapsulated is dispersed or dissolved in the polymer solution and the mixture of polymers and substance to be encapsulated in suspended in an aqueous solution. The organic solvent is removed by slow evaporation or spray drying to form the microsphere. Alternatively, the microspheres can be formed from a melt.
WO 2009/075652 to Nanyang Technological University, et al., describes a procedure for the formation of multi-walled microspheres involving emulsifying a first polymer solution in an organic solvent having at least one hydrophilic agent emulsified therein and a second solvent solution in an organic solvent; emulsifying the emulsion of the polymers and agent with an aqueous solution containing a stabilizer; and removing the organic solvents. This procedure requires multiple steps to form multiple emulsions.
Therefore, it is an object of the invention to provide compositions which exhibit increased uptake in the gastrointestinal tract.
It is a further object of the invention to provide methods for increasing the uptake in the gastrointestinal tract of active agents.
It is a further object of the invention to provide improved multi-walled nanoparticles, as well as improved methods for making multi-walled nanoparticles, particularly methods that form the nanoparticles in a minimum number of steps and do not require emulsification of the solvent.
It is yet a further object of the invention to provide improved multi-walled nanoparticles containing a bioadhesive layer.